Parkinson's disease (PD) is a neurodegenerative disorder in which deficits of the primary intracellular antioxidant, glutathione (GSH), are postulated to mediate increased oxidative stress and mitochondrial dysfunction in the pathogenic cascade leading up to the loss of nigrostriatal dopaminergic neurons that is the hallmark of the disorder. Therefore, there is currently great interest in treatment strategies that can maintain, restore and/or elevate intracellular GSH levels. However, GSH does not readily cross the blood-brain barrier or the membranes of most cells, including neurons, so that direct dietary supplementation of the antioxidant has not proved viable in increasing its intracellular concentration. On the other hand, since the bioavailability of cysteine, which does cross both the blood-brain barrier and most cell membranes, is rate-limiting in the GSH synthesis pathway, this amino acid and its non-toxic derivatives, such as N-acetylcysteine (NAC), are being investigated as potential precursors that can be supplied through dietary means to spur in situ synthesis and elevation of brain GSH. The overall objective of this Exploratory/Developmental (R21) study is to use noninvasive proton magnetic resonance spectroscopy (1H MRS) to determine (a) whether levels of GSH are decreased in vivo in the brain of 30 patients with Parkinson's disease (PD) compared to matched controls, as has been found in postmortem brain;(b) whether GSH levels in PD brain increase significantly following 30 days of daily supplementation with 2000mg or 4000mg of NAC compared to baseline and placebo, and (c) whether any such increases in brain GSH would be dose-dependent and be associated with a change in the participants'oxidative stress profiles. Additionally, a clinical assessment battery, including quantitative tests of motor function, will be performed to investigate potential associations between the NAC intervention, brain GSH levels, oxidative stress markers, and clinical presentation. If successful, this study will represent the first objective documentation of whether there is a GSH deficit in living PD brain that dietary NAC supplementation can mitigate, thereby providing a compelling justification for investigating such neuroprotective strategies in larger controlled clinical trials. PUBLIC HEALTH RELEVANCE: The overall objective of this study is to use noninvasive proton magnetic resonance spectroscopy (1H MRS) to determine (a) whether levels of the antioxidant glutathione (GSH) are decreased in vivo in the brain of 30 patients with Parkinson's disease (PD) compared to matched controls, as has been found in postmortem brain;(b) whether GSH levels in PD brain increase significantly following 30 days of daily supplementation with 2000mg or 4000mg of N- acetylcysteine (NAC) compared to placebo and baseline, and (c) whether any such increases in brain GSH would be dose-dependent and be associated with a change in the participants'oxidative stress profiles. Additionally, a clinical assessment battery, including quantitative tests of motor function, will be performed to investigate potential associations between the NAC intervention, brain GSH levels, oxidative stress markers, and clinical presentation. If successful, this study will represent the first objective documentation of whether there is a GSH deficit in living PD brain that dietary NAC supplementation can mitigate, thereby providing a compelling justification for investigating such neuroprotective strategies in larger controlled clinical trials.